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Vascular Endothelial Dysfunction and Mortality Risk in
Patients With Chronic Heart Failure
Stuart D. Katz, MD; Katarzyna Hryniewicz, MD; Ingrid Hriljac, MD; Kujtim Balidemaj, MD;
Clarito Dimayuga, MD; Alhakam Hudaihed, MD; Aleksandr Yasskiy, MD
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Background—Endothelial function is known to be impaired in subjects with chronic heart failure (CHF), but
the association between endothelial function and subsequent mortality risk in CHF has not been previously
reported.
Methods and Results—Biomarkers of endothelial function in the systemic arterial circulation (flow-mediated dilation
[FMD] in the brachial artery) and the pulmonary circulation (exhaled nitric oxide [NO] production during submaximal
exercise) were prospectively assessed in 259 subjects with New York Heart Association class II–III CHF. In subjects
with FMD measurements (n⫽149), there were 12 deaths and 5 urgent transplantations over a median follow-up period
of 841 days. In subjects with exhaled NO production measurements (n⫽110), there were 18 deaths and 1 urgent
transplantation over a median follow-up period of 396 days. Both decreased FMD and decreased exhaled NO production
were associated with increased risk of death or urgent transplantation after adjustment for other known CHF prognostic
factors (age, etiology of CHF, functional class, left ventricular ejection fraction) in Cox multivariate proportionalhazards models (adjusted hazard ratio [HR] estimate for a 1% decrease in FMD⫽1.20; 95% confidence interval [CI],
1.03 to 1.45; P⫽0.027; adjusted HR estimate for a 1-ppb/min decrease in exhaled NO production⫽1.31, 95% CI, 1.01
to 1.69, P⫽0.04).
Conclusions—Endothelial dysfunction in CHF, as assessed by FMD in the brachial artery and exhaled NO production
during submaximal exercise, is associated with an increased mortality risk in subjects with both ischemic and
nonischemic CHF. (Circulation. 2005;111:310-314.)
Key Words: nitric oxide 䡲 endothelium 䡲 heart failure 䡲 survival
E
ndothelium-dependent, nitric oxide (NO)–mediated
vasodilation in response to hormonal agonists and/or
shear stress is decreased in the skeletal muscle, coronary,
and pulmonary circulations of patients with chronic heart
failure (CHF) when compared with healthy subjects.1–3
Impaired endothelium-dependent vasodilation in patients
with CHF is attributable to decreased activity of the
L-arginine–NO synthetic pathway, increased degradation
of NO by reactive oxygen species, and hyporesponsiveness
in vascular smooth muscle.4 – 6 Impaired endothelial function is known to be associated with reduced exercise
hyperemia and impaired functional capacity,7,8 but its
association with clinical outcomes has not been previously
reported.
The present study was undertaken to prospectively determine the association of 2 biomarkers of endothelial function,
flow-mediated dilation (FMD) in the brachial artery and
exhaled NO production during submaximal exercise, and
subsequent mortality risk in subjects with CHF.
Methods
Study Population
Two hundred fifty-nine ambulatory subjects with CHF were sequentially recruited in 2 separate cohorts: 149 subjects for determination
of FMD measurements and 110 subjects for determination of exhaled
NO production during submaximal exercise. Eligible subjects had
stable New York Heart Association (NYHA) functional classification II–III symptoms ⱖ3 months and left ventricular ejection fraction
ⱕ40%. Patients with exercise-limiting coronary artery disease or
peripheral vascular disease, renal disease (serum creatinine ⬎3.0
mg/dL), liver disease (liver enzyme tests ⬎3 times the upper limit of
normal), chronic lung disease, or chronic inflammatory diseases
were excluded. Background therapy with digoxin, diuretics, angiotensin-converting enzyme inhibitors, nitrates, and/or ␤-adrenergic
receptor blockers was discontinued on the morning of testing. Study
protocols were approved by the Columbia University and Yale
University Ethical Review Committees. All subjects provided written, informed consent before participation.
Brachial Artery Ultrasound Imaging
Endothelium-dependent, flow-mediated dilation of the brachial artery was determined with high-resolution ultrasound imaging (Ad-
Received April 30, 2004; revision received September 15, 2004; accepted September 24, 2004.
From the Department of Internal Medicine (S.D.K., K.H., A.H., A.Y.), Yale University School of Medicine, New Haven, Conn, and the Department
of Medicine (I.H., K.B., C.D.), Columbia University College of Physicians and Surgeons, New York, NY.
Correspondence to Stuart D. Katz, MD, Yale University School of Medicine, 135 College St, Ste 301, New Haven, CT 06510. E-mail
[email protected]
© 2005 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org
DOI: 10.1161/01.CIR.0000153349.77489.CF
310
Katz et al
vanced Technology Laboratories) adapted from published guidelines
as previously described.9,10 Brachial artery diameter was determined
as the mean of 5 measurements from a single cardiac cycle at
end-diastole at rest and 60 to 75 seconds after release of a 5-minute
forearm cuff occlusion. FMD was calculated as the percent change in
brachial artery diameter after forearm cuff release compared with the
resting brachial artery diameter. Brachial artery blood flow velocity
(cm/s) was determined with a 1.2-mm, pulsed-Doppler sampling
volume in the vessel lumen midline with software correction for the
incident angle of 60° at rest and for the first 15 seconds after forearm
cuff release. The mean blood flow velocity over 5 cardiac cycles is
reported.
Determination of NO Production in Expired Gases
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Subjects breathed by mouth through a low-resistance, 3-way valve
from a 500-L reservoir of NO-free air with a nose clip to exclude
nasopharyngeal sources of NO.11 In a preliminary study of 10 CHF
subjects, inhalation of aerosolized NG-monomethyl-L-arginine did
not alter exhaled NO production when compared with placebo,
confirming a lower-airway source for exhaled NO in these patients.
NO in expired gases (ppb) was measured with a calibrated chemiluminescent NO analyzer (Sievers model 280). Ventilation (L/min)
was simultaneously measured with a calibrated pneumotachometer.
NO production (ppb/min) was calculated as the product of the
phase-corrected NO concentration and the ventilation signals. Because minute ventilation has been previously reported to influence
NO mass transfer from alveoli,11,12 all exhaled NO production
measurements were determined at submaximal work rates individually adjusted to correspond to a standardized minute ventilation of 20
L/min. Subjects continued steady-state submaximal exercise at the
target work rate for 5 minutes until a plateau in NO production was
present. The average exhaled NO production in the last minute of
exercise is reported.
Patient Outcomes Determination
Patient outcomes (death, urgent cardiac transplantation, or no event)
were determined for all patients by direct contact with the patient,
his/her family, or physician. Subjects of the cohort with exhaled NO
production measurements were enrolled between January 1998 and
January 1999, and vital status was determined for all subjects of the
cohort as of August 1, 1999. Subjects of the cohort with FMD
measurements were enrolled between May 2000 and January 2003,
and vital status was determined for all subjects of the cohort as of
May 16, 2003.
Endothelial Function and Mortality in CHF
311
TABLE 1. Clinical Characteristics of 149 Study Subjects in
Cohort With FMD Measurements
Age, y
All Subjects
(n⫽149)
Survivors
(n⫽132)
Nonsurvivors
(n⫽17)
54⫾1
54⫾1
57⫾3
Sex, % male
84
84
82
Etiology, % ischemic
33
29
65
Class II
51
55
23
Class III
49
45
76
0.25⫾0.01
0.25⫾0.01
0.25⫾0.04
Diabetes
20
17
38
Hypertension
25
24
38
Hyperlipidemia
27
25
44
Never
41
42
34
Past history
48
48
53
Current
11
10
13
100
100
100
55
56
47
NYHA class, %
Left ventricular ejection fraction
Comorbidities, %
Smoking
Medications, %
RAS inhibitors
␤-Blockers
Nitrates
4
2
18
Brachial artery diameter, mm
4.11⫾0.06
4.13⫾0.06
4.03⫾0.15
FMD, %
2.31⫾0.27
2.55⫾0.29
0.47⫾0.60
Rest MBFV, cm/s
6.8⫾0.3
7.0⫾0.4
5.9⫾0.8
Peak MBFV, cm/s
50⫾1.9
51⫾1.2
48⫾4.7
RAS indicates renin-angiotensin system; MBFV, mean blood flow velocity. All
other abbreviations are as defined in text.
value of 1.79%, subjects with lower values of FMD had
significantly more events (n⫽13) than did subjects with
higher values of FMD (n⫽4, Figure 1; P⫽0.01, log-rank
test). In Cox proportional-hazards models adjusted for other
Data Analysis
All values are presented as mean⫾SEM. Survival data were analyzed by the Kaplan-Meier method, log-rank tests for univariate
analyses, and Cox proportional-hazards models for multivariate
analyses (Stata biostatistical software, version 8.0).13 Known prognostic indicators (age, etiology of CHF, NYHA class, left ventricular
ejection fraction) were included in all Cox multivariate models.
Proportional-hazards assumptions were tested in final models based
on analysis of Schoenfeld residuals.14 With an assumed annual event
rate of 20%, 1-year accrual with 2-year follow-up, and 2-tailed
␣⫽0.05, the power to detect 2-fold and 3-fold risk differences in
groups above and below the median value was 63% and 94%,
respectively, for the 110 subjects with exhaled NO production
measurements and 76% and 98%, respectively, for the 149 subjects
with FMD measurements. For all analyses, a probability value ⬍0.05
was used to infer statistical significance.
Results
FMD Cohort
Clinical characteristics of survivors and nonsurvivors are
provided in Table 1. There were 12 deaths and 5 urgent
transplantations over a median follow-up period of 841 days.
When grouped by FMD responses above or below the median
Figure 1. Kaplan-Meier plot showing proportion of survivors
over time in subjects with FMD above (dashed line) and below
(solid line) median value of 1.79%. Subjects with lower FMD values had more events (n⫽13) than did subjects with higher FMD
values (n⫽4; P⫽0.01, by log-rank test). Abbreviations are as
defined in text.
312
Circulation
January 25, 2005
TABLE 2. Clinical Characteristics of 110 Subjects With
Measurements of Exhaled NO Production During
Submaximal Exercise
Age, y
All Subjects
(n⫽110)
Survivors
(n⫽91)
Nonsurvivors
(n⫽19)
58⫾1
58⫾1
58⫾3
Sex, % male
82
80
89
Etiology, % ischemic
56
53
57
Class II
54
54
53
Class III
46
46
47
0.25⫾0.01
0.25⫾0.01
0.26⫾0.03
Diabetes
34
33
37
Hypertension
35
42
34
Hyperlipidemia
29
29
32
Never
40
41
33
Past history
56
55
61
4
4
7
NYHA class, %
Left ventricular ejection fraction
Comorbidities, %
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Smoking
Current
Medications, %
100
100
100
␤-Blockers
RAS inhibitors
56
55
63
Nitrates
19
19
19
4.3⫾0.19
4.5⫾0.22
3.6⫾0.43
21⫾0.6
21⫾0.7
22⫾1.2
Exhaled NO, ppb/min
Ventilation, L/min
Abbreviations are as defined in text and in the footnote to Table 1.
known prognostic factors, decreased FMD remained significantly associated with increased mortality risk when considered as a continuous variable (adjusted hazard ratio [HR]
estimate for a 1% decrease in FMD⫽1.20; 95% confidence
interval [CI], 1.03 to 1.45; P⫽0.027) or dichotomized at the
median value (adjusted HR estimate for below median
FMD⫽3.45; 95% CI, 1.10 to 11.1; P⫽0.033).
Exhaled NO Production Cohort
Clinical characteristics of survivors and nonsurvivors are
provided in Table 2. There were 18 deaths and 1 urgent
transplantation over a median follow-up period of 396 days.
When grouped by exhaled NO production responses above or
below the median value of 4.1 ppb/min, subjects with lower
values of NO production had more events (n⫽13) than did
subjects with higher values of NO production (n⫽6, Figure 2;
P⫽0.05 by log-rank test). In Cox proportional-hazards models adjusted for other known prognostic factors, decreased
exhaled NO production was significantly associated with
increased mortality risk when considered as a continuous
variable (adjusted HR estimate for a 1-ppb/min decrease in
exhaled NO production⫽1.31; 95% CI, 1.01 to 1.69;
P⫽0.04) or dichotomized at the median value (adjusted HR
estimate for below median exhaled NO production⫽2.82;
95% CI, 1.04 to 7.63; P⫽0.04).
Discussion
The present findings demonstrate that impaired vascular
endothelial function, as evidenced by decreased FMD in the
Figure 2. Kaplan-Meier plot showing proportion of survivors
over time in subjects with exhaled NO production above
(dashed line) and below (solid line) median value of 4.1 ppb/min.
Subjects with lower values of NO production had more events
(n⫽13) than did subjects with higher values of NO production
(n⫽6; P⫽0.05, by log-rank test). Abbreviations are as defined in
text.
brachial artery and decreased exhaled NO production during
submaximal exercise, is associated with increased mortality
risk in CHF subjects after adjustment for other known clinical
prognostic factors.
Previous experimental and clinical studies have demonstrated impaired endothelium-dependent vasodilation in coronary, skeletal muscle, and pulmonary circulations in patients
with CHF.1–3,15,16 In the present study, FMD was used as an
indirect biomarker of endothelial function, because this response is partly dependent on shear stress–induced release of
NO.17 FMD is also regulated by local prostaglandin production, by the effects of local metabolic conditions on
hemoglobin-NO interactions, and by systemic effects related
to inflammation, sympathetic activation, and deconditioning.18 –23 The present study design cannot determine which
regulatory component(s) of the FMD response might be
linked to disease progression in CHF. The relative roles of
endothelial cell dysfunction and vascular smooth muscle
dysfunction cannot be discerned from our study, because
nitroglycerin responses were not recorded. FMD in the
brachial artery is closely associated with endotheliumdependent vasomotion in the coronary circulation and is
thought to be associated with proinflammatory and prothrombotic changes in endothelial cell phenotype.24 –26 In subjects
with ischemic CHF, the association between endothelial
dysfunction and mortality could be related to an increased
risk of ischemic events, as has been previously described in
patients with coronary artery disease and peripheral vascular
disease.27 Other mechanisms are also likely contributory,
because the observed association between endothelial function and mortality was independent of CHF etiology. Endothelial dysfunction in the coronary microcirculation could
contribute to disease progression by inducing local areas of
ischemia and/or necrosis.28 Endothelial dysfunction may be
also be linked to vasculature-dependent changes in ventricular loading conditions that could promote ventricular remodeling and disease progression.29
Katz et al
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NO increases in response to exercise in the healthy human
and is thought to play an important role in the normal
regulation of smooth muscle tone in pulmonary airways and
blood vessels.11,30 –33 Experimental and clinical studies have
demonstrated that NO may be derived from endothelial,
epithelial, and inflammatory cells present throughout the
respiratory tract.11,34 –36 Studies in isolated lung preparations
and the intact human respiratory tract have demonstrated that
a portion of NO in expired gases is derived from the lower
respiratory tract, including alveolae.37– 40 Increased exhaled
NO production in response to exercise may be attributed to
increased shear stress–induced release of NO from alveolar
endothelial cells and increased exercise hyperventilationdependent mass transport of NO from alveoli.11,41,42 Airway
inflammation may also contribute to exhaled NO production.36,43,44 In patients with CHF, decreased exhaled NO
production during exercise is associated with increased pulmonary vascular resistance and decreased maximal aerobic
capacity.41,45– 48 Decreased exhaled NO production in patients
with CHF may be attributed to decreased diffusion/transport
of NO from lower-airway sources and/or a reduced rate of
cellular production of NO in the lower respiratory
tract.4,40,49 –52 Increased mortality risk in association with
decreased exhaled NO production could be related to autonomic dysregulation of ventilation during exercise, progression of right ventricular dysfunction in response to increased
pulmonary vascular resistance, or other hemodynamic factors
associated with decreased aerobic capacity.41,47,48,53
Interpretation of our findings is potentially limited by
several considerations. Although our findings with 2 biomarkers of endothelial function and subsequent mortality risk are
internally consistent in our study cohorts, the observational
nature of the study does not allow one to draw conclusions
regarding a causal link between endothelial dysfunction and
mortality, because unmeasured confounders may have contributed to the observed associations. Our study sample was
recruited from a tertiary referral heart failure and transplantation center and therefore may not be representative of CHF
patients in the general community. The sample size and
relatively small number of events limited the number of
variables in our regression models and provided sufficient
statistical power to detect only large risk differences with
wide CIs. Although our reported associations were adjusted
for several known prognostic factors, we were unable to
adjust our findings for other important prognostic indicators,
including left ventricular end-diastolic diameter, peak aerobic
capacity, implantable cardioverter-defibrillator use, and biomarkers of neurohormonal activation, because these data
were unavailable for all of our subjects. Additional work in a
larger study sample is warranted to determine whether endothelial dysfunction is independently associated with mortality
after adjustment for these other known prognostic factors.
Additional data on the association between endothelial function and cardiovascular disease–specific mortality and major
cardiac disease–related morbidities, including nonfatal myocardial infarction and hospitalization for CHF, are also
needed. Although discontinued for 12 to 24 hours before all
study measurements, background medications may have contributed to our findings.
Endothelial Function and Mortality in CHF
313
In conclusion, these data provide the first evidence of an
association between markers of endothelial function and
subsequent clinical outcomes in patients with CHF. Additional work is needed to determine the underlying mechanisms and potential therapeutic implications of these findings.
Acknowledgments
This study was supported in part by an American Heart Association
(Heritage Affiliate) Grant-In-Aid and NHLBI grants HL K24-04024
(S.D.K.) and HL R01-51433 (S.D.K.).
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Vascular Endothelial Dysfunction and Mortality Risk in Patients With Chronic Heart
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Stuart D. Katz, Katarzyna Hryniewicz, Ingrid Hriljac, Kujtim Balidemaj, Clarito Dimayuga,
Alhakam Hudaihed and Aleksandr Yasskiy
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Circulation. 2005;111:310-314; originally published online January 17, 2005;
doi: 10.1161/01.CIR.0000153349.77489.CF
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